TRIM24 Up-Regulates ORM2 to Alleviate Abnormal Lipid Metabolism, Inflammation, and Oxidative Stress in Mice with Obstructive Sleep Apnea Syndrome and Metabolic Dysfunction–Associated Steatotic Liver Disease

Abstract

Obstructive sleep apnea syndrome (OSAS) is associated with the development and progression of metabolic dysfunction–associated steatotic liver disease (MASLD). Tripartite motif containing 24 (TRIM24) deficiency causes hepatic lipid accumulation and hepatitis. However, the expression, function, and mechanism of TRIM24 in OSAS and MASLD remain unclear. Herein, an OSAS and MASLD mouse model was established by intermittent hypoxia (IH) and high-fat diet. IH- and 1% free fatty acid–induced mouse liver cells served as an in vitro model. TRIM24 and HIF1A were up-regulated under the IH condition. HIF1A enhanced the transcriptional activity of TRIM24. Overexpression of TRIM24 reduced hepatic lipid accumulation, decreased serum levels of total cholesterol, triglyceride, and low-density lipoprotein cholesterol, and increased serum levels of high-density lipoprotein cholesterol in OSAS and MASLD mice. Additionally, overexpression of TRIM24 alleviated inflammation and oxidative stress, and modulated aberrant lipid metabolism. Mechanically, TRIM24 up-regulated the expression of ORM2, a key regulator of hepatic lipogenesis, by binding to H3K27ac and recruiting retinoic acid receptor-α to ORM2 promoter. The cell rescue model was used to verify that ORM2 mediated the hepatoprotective effects of TRIM24. The current study reveals the important role of TRIM24 as an epigenetic coregulator of transcription in OSAS and MASLD, providing additional insights into understanding the pathogenesis and preventing the development of OSAS and MASLD.